It is estimated that approximately 22,000 new cases of ovarian cancer will be diagnosed in 2012 (American Cancer Society Statistics). These patients typically undergo a combination of surgery, chemotherapy and radiation treatment. Many of the current chemotherapeutic drugs bind to, or are incorporated into, DNA, which ultimately blocks DNA replication and transcription. The accumulation of damaged DNA blocks cell progression that leads to an apoptotic response.
One of the limitations of chemotherapy in ovarian cancer, however, is that many cancers have innate drug resistance or acquire drug resistance. There are several mechanisms responsible for the development of drug resistance, including decreased drug accumulation, increased drug inactivation/sequestering by thiols, and increased DNA repair. Increased DNA repair has been shown to be a major mechanism of cancer drug resistance, including in patient samples following cisplatin treatment. The enhanced DNA repair that is observed in cancers occurs early in the development of resistance, appears to be one of the first mechanisms activated, and it is evident in nearly all cases of high cisplatin resistance.
With respect to chemotherapy and effects on cancer treatment, repair of the damaged DNA induced by the chemotherapy is detrimental to the efficacy of the drugs. This is supported by the fact that DNA repair deficient cells are hypersensitive to many chemotherapeutic agents, including cisplatin.
Ovarian cancer is typically treated with a combination of surgery and chemotherapy. One of the biggest problems in regard to killing the ovarian cancer cells is drug resistance. This resistance can be seen prior to the initial treatment or as a consequence of drug therapy. Many chemotherapeutic drugs, including cisplatin, function by binding to DNA and inhibiting cells from replicating and dividing. This ultimately inhibits cancer cell growth and leads to cell death. Ovarian cancers, as well as other cancers that are resistant to cisplatin, often have pathways in place or develop ways to remove the drug from DNA to avoid cell death. DNA repair pathways can be up-regulated in resistant cancers and remove cisplatin from the DNA.
With respect to cisplatin DNA repair, nucleotide excision repair (NER) is the primary pathway for the removal of the abundant intrastrand DNA adducts. It is now believed that both NER and homologous recombination (HR) play critical roles in the repair of cisplatin DNA interstrand crosslinks (ICLs).
Cells typically have multiple mechanisms and pathways to deal with the chemotherapeutic drugs directed toward killing tumors. The current chemotherapeutic drugs do not selectively target cancer cells which, as a consequence, typically leads to toxic side effects by targeting normal cells. If a particular cancer is mutated in one of two pathways required for the repair of a specific chemotherapeutic agent, then by targeting the other pathway, the cancers would be selectively targeted with chemotherapy.
In this scenario, normal cells will be minimally affected and have reduced side effects as the alternate pathway of drug removal is still functional. One way to selectively target cancer cells is to take advantage of specific mutations that have arisen as a consequence of tumorigenesis and loss of heterozygosity (LOH).
In spite of considerable research into therapies to treat such diseases, it remains difficult to treat effectively, and the mortality observed in patients indicates that improvements are needed in the diagnosis, treatment and prevention of such diseases.